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Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
Avibactam is a potent β-lactamase inhibitor employed in the treatment of different disorders including abdominal infections, urinary tract infections and hospital acquired pneumonia, among others. Very recently, a chemoenzymatic strategy has been disclosed based on the hydrolytic resolution of a 97:3 cis/trans-mixture of ethyl 5-hydroxypiperidine-2-carboxylate using a 353 g scale (Wang et al., 2018). Lipozyme CAL-B led to the ethyl (2S,5S)-5-hydroxypiperidine-2-carboxylate as a single enantiomer and in diastereomerically pure form with concomitant formation of the hydroxy acid by-product (Scheme 9.7). The so-obtained aqueous layer was used without purification for the straightforward synthesis of Avibactam. Resolution of a key intermediate in the synthesis of Avibactam.
Aztreonam and Aztreonam-Avibactam
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Avibactam is a novel, non-beta-lactam/beta-lactamase inhibitor. Avibactam is capable of inhibiting class A, class C, and some class D beta-lactamases, including extended-spectrum beta-lactamases (ESBLs), AmpC, and serine carbapenemases such as Klebsiella pneumoniae carbapenemase (KPC) and OXA-48 type (Livermore et al., 2011). Although avibactam does not inhibit metallo-beta-lactamases (MBLs), the combination with aztreonam, which is not hydrolyzed by MBLs, is currently in clinical development against multidrug-resistant Gram-negative bacteria including MBLs (Bush, 2015).
Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies
Published in Expert Review of Anti-infective Therapy, 2022
Ilias Karaiskos, Irene Galani, Vassiliki Papoutsaki, Lamprini Galani, Helen Giamarellou
Avibactam is the first BLBLI implemented within the clinical setting. Avibactam is a potent inhibitor of class A, C, and certain D β-lactamases, however, shows poor activity against organisms producing MBLs. Most interestingly, avibactam is a reversible covalent inhibitor and thus has a unique mechanism of inhibition among all β-lactamase inhibitors. Avibactam forms a noncovalent complex with the enzyme, then acylates the enzyme to give a covalent complex. Subsequent deacylation of the covalent complex proceeds through reversible cyclization and regeneration of the active inhibitor rather than undergoing hydrolysis [15,21]. Avibactam has been approved in combination with the third-generation cephalosporin ceftazidime with activity against P. aeruginosa [33]. Avibactam is currently in clinical trial in combination with aztreonam for the treatment of serious infections caused by MBL producing Gram-negative bacteria (Phase 3, Clinicaltrial.gov identifier: NCT03580044). Aztreonam has activity against MBL-producing pathogens, but it can be hydrolyzed by most Ambler class A, C, and D serine β-lactamases [34]. Avibactam, however, inhibits Ambler class A, C, and some D β-lactamases broadening the in vitro spectrum of aztreonam-avibactam combination. Avibactam with ceftaroline fosamil, which is a fifth-generation broad-spectrum parenteral cephalosporin with MRSA activity has completed a Phase 2 clinical trial (Clinicaltrial.gov identifier: NCT01281462).
Evaluation of the post-antibiotic effect in vivo for the combination of a β-lactam antibiotic and a β-lactamase inhibitor: ceftazidime-avibactam in neutropenic mouse thigh and lung infections
Published in Journal of Chemotherapy, 2021
Johanna Berkhout, Maria J. Melchers, Anita C. van Mil, Claudia M. Lagarde, Wright W. Nichols, Johan W. Mouton
In conclusion, we have designed a method to study the PAE of β-lactam/β-lactamase inhibitor combinations, which has provided new information towards increasing the understanding of the PK/PD of such combinations. Specifically, we found no clear PAE for P. aeruginosa for the new drug combination of ceftazidime and avibactam in the neutropenic mouse thigh model used, consistent with earlier in vitro and in vivo studies,9,13,17 although a PAE was measurable in the lung infection model. Nonetheless, a persistent effect of the drug combination was visible in the thigh-infection model for 0.35–1 h after the concentrations of ceftazidime and avibactam declined to below their target values, which could be quantified as a ‘PAER’. Finally, we did not investigate the presence of any in vivo ‘post-β-lactamase inhibitor effect’ or PLIE. However, when sought in vitro, no consistent PLIE of avibactam in combination with ceftazidime could be discerned.9,13
The activity of ceftazidime/avibactam against carbapenem-resistant Pseudomonas aeruginosa
Published in Infectious Diseases, 2021
Carmen Antonia Sanches Ito, Larissa Bail, Lavinia Nery Villa Stangler Arend, Keite da Silva Nogueira, Felipe Francisco Tuon
In this journal attempts to circumvent carbapenem resistance of Pseudomonas aeruginosa were recently reported [1]. Among 28 clinical carbapenem-resistant isolates of P. aeruginosa, 14 were shown to be susceptible to a combination of ceftazidime and avibactam. Ceftazidime is a broad-spectrum cephalosporin with anti-pseudomonas activity. Currently, the susceptibility profile has been compromised due to extended-spectrum beta-lactamases (ESBL) and carbapenemases. Avibactam is a beta-lactamase inhibitor that acts on the enzymes AmpC, ESBL, KPC and some oxacillinases, restoring the activity of ceftazidime when combined. Avibactam is a beta-lactamase inhibitor that reversibly binds to these enzymes, allowing for the recycling and inhibition of additional beta-lactamase molecules [2].